UNDERSTANDING NEURAL DEVELOPMENT THROUGH MUTATIONS

我们正在使用影响小脑的经典小鼠神经学突变[摇摇欲坠(Tg)、神经(Nr)、Meandner Tail(MeA)]，结合反向遗传学，作为理解指导哺乳动物大脑发育的细胞和分子机制的模型系统。之所以选择TG小鼠进行研究，是因为它们是为数不多的失神癫痫小鼠模型之一。尽管一半的人类癫痫有遗传成分，多达1%的人患有癫痫，但还没有发现失神癫痫的基因。通过定位克隆，我们发现Tg编码Cacnl1a4电压敏感钙通道。同时，在发作性共济失调2(EA2)和家族性偏瘫偏头痛(FHM)患者中发现了人类CACNL1A4突变。未来的研究旨在了解这些疾病的病理生理学。之所以选择NR小鼠进行研究，是因为它们有一种不寻常的病理，最初包括线粒体的圆形和块状，以及小脑浦肯野神经元中内质网和高尔基体组织的破坏。随后，nr浦肯野细胞以条纹模式退化，这是在携带较瘦等位基因的TG小鼠中发现的浦肯野细胞退化的镜像。目前正在进行位置克隆实验，以确定由nr基因座编码的基因。之所以选择MEA小鼠，是因为它们的形态发生缺陷似乎定义了以前没有通过组织学或功能标准定义的小脑的一个离散的隔室。未来的研究旨在对mea基因产物进行定位克隆。

We are using classical mouse neurological mutations [tottering (tg), nervous (nr), meandner tail (mea)] that affect the cerebellum, combined with reverse genetics, as a model system for understanding the cellular and molecular mechanisms that guide development of the mammalian brain. The tg mice were chosen for study because they are one of the few mouse models for absence epilepsy. Although half of all human epilepsies have a genetic component, and as much as 1% of the population suffers from epilepsy, no genes had been identified for absence epilepsy. By positional cloning, we showed that tg encodes the Cacnl1a4 voltage-sensitive calcium channel. Contemporaneously, mutations in human CACNL1A4 were found in patients with episodic ataxia 2 (EA2) and familial hemiplegic migraine (FHM). Future studies are aimed at understanding the pathophysiology of these diseases. nr mice were chosen for study because they have an unusual pathology that initially includes rounding and clumping of the mitochondria and a disruption in the organization of the ER and Golgi in cerebellar Purkinje neurons. Subsequently, nr Purkinje cells degenerate in a striped pattern that is the mirror image of the Purkinje cell degeneration found in tg mice carrying the leaner allele. Positional cloning experiments are currently underway to identify the gene encoded by the nr locus. mea mice were chosen because they have a morphogenetic defect that appears to define a discrete compartment of the cerebellum that has not been previously defined by histological or functional criteria. Future studies are aimed at positionally cloning the mea gene product.